Heterocyclyl-3-sulfonylazaindole or-azaindazole derivatives as 5-hydroxytryptamine-6 ligands

ABSTRACT

The present invention provides a compound of formula I and the use thereof for the treatment of a central nervous system disorder related to or affected by the 5-HT6 receptor.

BACKGROUND OF THE INVENTION

[0001] This application claims priority from provisional application No.60/447515 filed on Feb. 14, 2003, the entire disclosure of which ishereby incorporated by reference.

[0002] Serotonin (5-Hydroxytryptamine)(5-HT) receptors play a criticalrole in many physiological and behavioral functions in humans andanimals. These functions are mediated through various 5-HT receptorsdistributed throughout the body. There are now approximately fifteendifferent human 5-HT receptor subtypes that have been cloned, many withwell-defined roles in humans. One of the most recently identified 5-HTreceptor subtypes is the 5-HT6 receptor, first cloned from rat tissue in1993 (Monsma, F. J.; Shen, Y.; Ward, R. P.; Hamblin, M. W. MolecularPharmacology 1993, 43, 320-327) and subsequently from human tissue(Kohen, R.; Metcalf, M. A.; Khan, N.; Druck, T.; Huebner, K.; Sibley, D.R. Journal of Neurochemistry 1996, 66, 47-56). The receptor is aG-protein coupled receptor (GPCR) positively coupled to adenylatecyclase (Ruat, M.; Traiffort, E.; Arrang, J-M.; Tardivel-Lacombe, L.;Diaz, L.; Leurs, R.; Schwartz, J-C. Biochemical Biophysical ResearchCommunications 1993, 193, 268-276). The receptor is found almostexclusively in the central nervous system (CNS) areas both in rat and inhuman. In situ hybridization studies of the 5-HT6 receptor in rat brainusing mRNA indicate principal localization in the areas of 5-HTprojection including striatum, nucleus accumbens, olfactory tubercle,and hippocampal formation (Ward, R. P.; Hamblin, M. W.; Lachowicz, J.E.; Hoffman, B. J.; Sibley, D. R.; Dorsa, D. M. Neuroscience 1995,64,1105-1111).

[0003] There are many potential therapeutic uses for 5-HT6 ligands inhumans based on direct effects and on indications from availablescientific studies. These studies include the localization of thereceptor, the affinity of ligands with known in vivo activity, andvarious animal studies conducted so far.

[0004] One potential therapeutic use of modulators of 5-HT6 receptorfunction is in the enhancement of cognition and memory in human diseasessuch as Alzheimer's. The high levels of receptor found in importantstructures in the forebrain, including the caudate/putamen, hippocampus,nucleus accumbens, and cortex suggest a role for the receptor in memoryand cognition since these areas are known to play a vital role in memory(Gerard, C.; Martres, M.-P.; Lefevre, K.; Miquel, M. C.; Verge, D.;Lanfumey, R.; Doucet, E.; Hamon, M.; El Mestikawy, S. Brain Research,1997, 746, 207-219). The ability of known 5-HT6 receptor ligands toenhance cholinergic transmission also supported the potential cognitionuse (Bentley, J. C.; Boursson, A.; Boess, F. G.; Kone, F. C.; Marsden,C. A.; Petit, N.; Sleight, A. J. British Journal of Pharmacology, 1999,126(7), 1537-1542). Studies have found that a known 5-HT6 selectiveantagonist significantly increased glutamate and aspartate levels in thefrontal cortex without elevating levels of noradrenaline, dopamine, or5-HT. This selective elevation of neurochemicals known to be involved inmemory and cognition strongly suggests a role for 5-HT6 ligands incognition (Dawson, L. A.; Nguyen, H. Q.; Li, P. British Journal ofPharmacology, 2000, 130(1), 23-26). Animal studies of memory andlearning with a known selective 5-HT6 antagonist found some positiveeffects (Rogers, D. C.; Hatcher, P. D.; Hagan, J. J. Society ofNeuroscience, Abstracts 2000, 26, 680). Further support for the role ofa selective 5-HT6 ligand in cognition can be found in Woolley, M. L.;Marsden, C. A.; Sleight, A. J.; and Fone, K. C. F., Psychopharmacology,2003, 170(4), 358-367.

[0005] A related potential therapeutic use for 5-HT6 ligands is thetreatment of attention deficit disorders (ADD, also known as AttentionDeficit Hyperactivity Disorder or ADHD) in both children and adults.Because 5-HT6 antagonists appear to enhance the activity of thenigrostriatal dopamine pathway and because ADHD has been linked toabnormalities in the caudate (Ernst, M; Zametkin, A. J.; Matochik, J.H.; Jons, P. A.; Cohen, R. M. Journal of Neuroscience 1998, 18(15),5901-5907), 5-HT6 antagonists may attenuate attention deficit disorders.

[0006] Early studies examining the affinity of various CNS ligands withknown therapeutic utility or a strong structural resemblance to knowndrugs suggests a role for 5-HT6 ligands in the treatment ofschizophrenia and depression. For example, clozapine (an effectiveclinical antipsychotic) has high affinity for the 5-HT6 receptorsubtype. Also, several clinical antidepressants have high affinity forthe receptor as well and act as antagonists at this site (Branchek, T.A.; Blackburn, T. P. Annual Reviews in Pharmacology and Toxicology 2000,40, 319-334).

[0007] Further, recent in vivo studies in rats indicate 5-HT6 modulatorsmay be useful in the treatment of movement disorders including epilepsy(Stean, T.; Routledge, C.; Upton, N. British Journal of Pharmacology1999, 127 Proc. Supplement 131P and Routledge, C.; Bromidge, S. M.;Moss, S. F.; Price, G. W.; Hirst, W.; Newman, H.; Riley, G.; Gager, T.;Stean, T.; Upton, N.; Clarke, S. E.; Brown, A. M. British Journal ofPharmacology 2000, 130(7), 1606-1612).

[0008] Taken together, the above studies strongly suggest that compoundswhich are 5-HT6 receptor modulators, i.e. ligands, may be useful fortherapeutic indications including: the treatment of diseases associatedwith a deficit in memory, cognition, and learning such as Alzheimer'sand attention deficit disorder; the treatment of personality disorderssuch as schizophrenia; the treatment of behavioral disorders, e.g.,anxiety, depression and obsessive compulsive disorders; the treatment ofmotion or motor disorders such as Parkinson's disease and epilepsy; thetreatment of diseases associated with neurodegeneration such as strokeand head trauma; or withdrawal from drug addiction including addictionto nicotine, alcohol, and other substances of abuse.

[0009] Therefore, it is an object of this invention to provide compoundswhich are useful as therapeutic agents in the treatment of a variety ofcentral nervous system disorders related to or affected by the 5-HT6receptor.

[0010] It is another object of this invention to provide therapeuticmethods and pharmaceutical compositions useful for the treatment ofcentral nervous system disorders related to or affected by the 5-HT6receptor.

[0011] It is a feature of this invention that the compounds provided mayalso be used to further study and elucidate the 5-HT6 receptor.

[0012] These and other objects and features of the invention will becomemore apparent by the detailed description set forth hereinbelow.

SUMMARY OF THE INVENTION

[0013] The present invention provides a heterocyclyl-3-sulfonylazaindoleor -azaindazole compound of formula I

[0014] wherein

[0015] W is N or CR₂;

[0016] X is N or CR₄;

[0017] Y is N or CR₅;

[0018] Z is N or CR₆;

[0019] Q is N or CR₇ with the proviso that at least one and not morethan two of X, Y, Z and Q must be N;

[0020] R₁ is an optionally substituted C₁-C₆alkyl, C₃-C₇cycloalkyl,aryl, or heteroaryl group or an optionally substituted 8- to 13-memberedbicyclic or tricyclic ring system having a N atom at the bridgehead andoptionally containing 1, 2 or 3 additional heteroatoms selected from N,O or S;

[0021] R₂ is H, halogen, or a C₁-C₆alkyl, C₁-C₆alkoxy, C₃-C₇cycloalkyl,aryl or heteroaryl group each optionally substituted;

[0022] R₃ is H or a C₁-C₆alkyl, C₃-C₇cycloalkyl, aryl or heteroarylgroup each optionally substituted;

[0023] R₄, R₅, R₆ and R₇ are each independently H, halogen, CN, COR₈,OCO₂R₉, CO₂R₁₀, CONR₁₁R₁₂, SO_(n)R₁₃, NR₁₄R₁₅, OR₁6 or a C₁-C₆alkyl,C₃-C₇cycloalkyl, aryl or heteroaryl group each optionally substituted ora group M having the structure

[0024]  with the proviso that at least one of R₄, R₅, R₆ or R₇ must be agroup M and with the further proviso that when W is CR₂ and X or Z is N,then R₇ must be other than a group M;

[0025] R₈, R₉, R₁₀ and R₁₃ are each independently H or a C₁-C₆alkyl,C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₆cycloalkyl, cycloheteroalkyl, aryl orheteroaryl group each optionally substituted;

[0026] R₁₁, R₁₂, R₁₄ and R₁₅ are each independently H or an optionallysubstituted C₁-C₄alkyl group or R₁₁ and R₁₂ or R₁₄and R₁₅ may be takentogether with the atom to which they are attached to form a 5- to7-membered ring optionally containing another heteroatom selected fromO, NR₂₂ or SO_(n);

[0027] R₁₆ is H or a C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,C₃-C₇cycloalkyl, cycloheteroalkyl, aryl or heteroaryl group eachoptionally substituted;

[0028] n is 0 or an integer of 1 or 2;

[0029] R₁₇ is H or a C₁-C₆alkyl or C₃-C₇cycloalkyl group each optionallysubstituted;

[0030] R₁₈, R₁₉, R₂₀, R₂₁ and R₂₃ are each independently H or aC₁-C₆alkyl or C₃-C₇cycloalkyl group each optionally substituted;

[0031] m is 1 or 2; and

[0032] R₂₂ is H or a C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,C₃-C₇cycloalkyl, cycloheteroalkyl, aryl or heteroaryl group eachoptionally substituted; or

[0033] the stereoisomers thereof or the pharmaceutically acceptablesalts thereof.

[0034] The present invention also provides methods and compositionsuseful for the therapeutic treatment of a central nervous systemdisorder related to or affected by the 5-HT6 receptor.

DETAILED DESCRIPTION OF THE INVENTION

[0035] The 5-hydroxytryptamine-6 (5-HT6) receptor is one of the mostrecent receptors to be identified by molecular cloning. Its ability tobind a wide range of therapeutic compounds used in psychiatry, coupledwith its intriguing distribution in the brain has stimulated significantinterest in new compounds which are capable of interacting with oraffecting said receptor. Significant efforts are being made tounderstand the possible role of the 5-HT6 receptor in psychiatry,cognitive dysfunction, motor function and control, memory, mood and thelike. To that end, compounds which demonstrate a binding affinity forthe 5-HT6 receptor are earnestly sought both as an aid in the study ofthe 5-HT6 receptor and as potential therapeutic agents in the treatmentof central nervous system disorders, for example see C. Reavill and D.C. Rogers, Current Opinion in Investigational Drugs, 2001, 2(1):104-109,Pharma Press Ltd.

[0036] Surprisingly, it has now been found thatheterocyclyl-3-sulfonylazaindole and -azaindazole derivatives of formulaI demonstrate 5-HT6 affinity. Advantageously, said azaindole andazaindazole derivatives may be used as effective therapeutic agents forthe treatment of central nervous system (CNS) disorders associated withor affected by the 5-HT6 receptor. Accordingly, the present inventionprovides 1-heterocyclyl-3-sulfonylazaindole and -azaindazole derivativesof formula I

[0037] wherein

[0038] W is N or CR₂;

[0039] X is N or CR₄;

[0040] Y is N or CR₅;

[0041] Z is N or CR₆;

[0042] Q is N or CR₇ with the proviso that at least one and not morethan two of X, Y, Z and Q must be N;

[0043] R₁ is an optionally substituted C₁-C₆alkyl, C₃-C₇cycloalkyl,aryl, or heteroaryl group or an optionally substituted 8- to 13-memberedbicyclic or tricyclic ring system having a N atom at the bridgehead andoptionally containing 1, 2 or 3 additional heteroatoms selected from N,O or S;

[0044] R₂ is H, halogen, or a C₁-C₆alkyl, C₁-C₆alkoxy, C₃-C₇cycloalkyl,aryl or heteroaryl group each optionally substituted;

[0045] R₃ is H or a C₁-C₆alkyl, C₃-C₇cycloalkyl, aryl, or heteroarylgroup each optionally substituted;

[0046] R₄, R₅, R₆ and R₇ are each independently H, halogen, CN, COR₈,OCO₂R₉, CO₂R₁₀, CONR₁₁R₁₂, SO_(n)R₁₃, NR₁₄R₁₅, OR₁₆ or a C₁-C₆alkyl,C₃-C₇cycloalkyl, aryl or heteroaryl group each optionally substituted ora group M having the structure

[0047]  with the proviso that at least one of R₄, R₅, R₆ or R₇ must be agroup M and with the further proviso that when W is CR₂ and X or Z is N,then R₇ must be other than a group M;

[0048] R₈, R₉, R₁₀ and R₁₃ are each independently H or a C₁-C₆alkyl,C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₆cycloalkyl, cycloheteroalkyl, aryl orheteroaryl group each optionally substituted;

[0049] R₁₁, R₁₂, R₁₄ and R₁₅ are each independently H or an optionallysubstituted C₁-C₄alkyl group or R₁₁, and R₁₂ or R₁₄ and R₁₅ may be takentogether with the atom to which they are attached to form a 5- to7-membered ring optionally containing another heteroatom selected fromO, NR₂₂ or SO_(n);

[0050] R₁₆ is H or a C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,C₃-C₇cycloalkyl, cycloheteroalkyl, aryl or heteroaryl group eachoptionally substituted;

[0051] n is 0 or an integer of 1 or 2;

[0052] R₁₇ is H or a C₁-C₆alkyl or C₃-C₇cycloalkyl group each optionallysubstituted;

[0053] R₁₈, R₁₉, R₂₀, R₂₁ and R₂₃ are each independently H or aC₁-C₆alkyl or C₃-C₇cycloalkyl group each optionally substituted;

[0054] m is 1 or 2; and

[0055] R₂₂ is H or a C₁-C6alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,C₃-C₇cycloalkyl, cycloheteroalkyl, aryl or heteroaryl group eachoptionally substituted; or

[0056] the stereoisomers thereof or the pharmaceutically acceptablesalts thereof.

[0057] As used in the specification and claims, the term halogendesignates F, Cl, Br or I and the term cycloheteroalkyl designates afive- to seven-membered cycloalkyl ring system containing 1 or 2heteroatoms, which may be the same or different, selected from N, O or Sand optionally containing one double bond. Exemplary of thecycloheteroalkyl ring systems included in the term as designated hereinare the following rings wherein X is NR, O or S; and R is H or anoptional substituent as described hereinbelow:

[0058] Similarly, as used in the specification and claims, the termheteroaryl designates a five- to ten-membered aromatic ring systemcontaining 1, 2 or 3 heteroatoms, which may be the same or different,selected from N, O or S. Such heteroaryl ring systems include pyrrolyl,azolyl, oxazolyl, thiazolyl, imidazolyl, furyl, thienyl, quinolinyl,isoquinolinyl, indolyl, benzothienyl, benzofuranyl, benzisoxazolyl orthe like. The term aryl designates a carbocyclic aromatic ring systemsuch as phenyl, naphthyl, anthracenyl or the like. The term haloalkyl asused herein designates a C_(n)H_(2n+1) group having from one to 2n+1halogen atoms which may be the same or different and the term haloalkoxyas used herein designates an OC_(n)H_(2n+1) group having from one to2n+1 halogen atoms which may be the same or different.

[0059] Exemplary of the 8- to 13-membered bicyclic or tricyclic ringsystems having a N atom at the bridgehead and optionally containing 1, 2or 3 additional heteroatoms selected from N, O or S included in the termas designated herein are the following ring systems wherein W₂ is NR, Oor S; and R is H or an optional substituent as described hereinbelow:

[0060] In the specification and claims, when the terms C₁-C₆alkyl,C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₇cycloalkyl, cycloheteroalkyl, aryl orheteroaryl as designated as being optionally substituted, thesubstituent groups which are optionally present may be one or more ofthose customarily employed in the development of pharmaceuticalcompounds or the modification of such compounds to influence theirstructure/activity, persistence, absorption, stability or otherbeneficial property. Specific examples of such substituents includehalogen atoms, nitro, cyano, thiocyanato, cyanato, hydroxyl, alkyl,haloalkyl, alkoxy, haloalkoxy, amino, alkylamino, dialkylamino, formyl,alkoxycarbonyl, carboxyl, alkanoyl, alkylthio, alkylsuphinyl,alkylsulphonyl, carbamoyl, alkylamido, phenyl, phenoxy, benzyl,benzyloxy, heterocyclyl or cycloalkyl groups, preferably halogen atomsor lower alkyl or lower alkoxy groups. Typically, 0-3 substituents maybe present. When any of the foregoing substituents represents orcontains an alkyl substituent group, this may be linear or branched andmay contain up to 12, preferably up to 6, more preferably up to 4 carbonatoms.

[0061] Pharmaceutically acceptable salts may be any acid addition saltformed by a compound of formula I and a pharmaceutically acceptable acidsuch as phosphoric, sulfuric, hydrochloric, hydrobromic, citric, maleic,malonic, mandelic, succinic, fumaric, acetic, lactic, nitric, sulfonic,p-toluene sulfonic, methane sulfonic acid or the like.

[0062] Compounds of the invention include esters, carbamates or otherconventional prodrug forms, which in general, are functional derivativesof the compounds of the invention and which are readily converted to theinventive active moiety in vivo. Correspondingly, the method of theinvention embraces the treatment of the various conditions describedhereinabove with a compound of formula I or with a compound which is notspecifically disclosed but which, upon administration, converts to acompound of formula I in vivo. Also included are metabolites of thecompounds of the present invention defined as active species producedupon introduction of these compounds into a biological system.

[0063] Compounds of the invention may exist as one or morestereoisomers. The various stereoisomers include enantiomers,diastereomers, atropisomers and geometric isomers. One skilled in theart will appreciate that one stereoisomer may be more active or mayexhibit beneficial effects when enriched relative to the otherstereoisomer(s) or when separated from the other stereoisomer(s).Additionally, the skilled artisan knows how to separate, enrich orselectively prepare said stereoisomers. Accordingly, the presentinvention comprises compounds of Formula I, the stereoisomers thereofand the pharmaceutically acceptable salts thereof. The compounds of theinvention may be present as a mixture of stereoisomers, individualstereoisomers, or as an optically active or enantiomerically pure form.

[0064] Preferred compounds of the invention are those compounds offormula I wherein m is 1. Also preferred are those compounds of formulaI wherein Y is CR₅ and R₅ is a group M. Another group of preferredcompounds of formula I are those compounds wherein W is N; Q is CR₇ andR₇ is a group M.

[0065] More preferred compounds of the invention are those formula Icompounds wherein m is 1; Y is CR₅ and R₅ is a group M. Another group ofmore preferred compounds are those formula I compounds wherein W is N; mis 1; Q is CR₇ and R₇ is a group M. Further more preferred formula Icompounds are those compounds wherein m is 1; R₅ is a group M and R₁ isan optionally substituted phenyl, naphthyl or heteroaryl group.

[0066] Examples of preferred compounds of formula I include:

[0067]5-(4-benzylpiperazin-1-yl)-3-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine;

[0068]5-(4-methylpiperazin-1-yl)-3-(phenylsulfonyl)-1H-pyrrolo[2,3-c]pyridine;

[0069]3-(phenylsulfonyl)-5-(4-propylpiperazin-1-yl)-1H-pyrrolo[2,3-b]pyridine;

[0070] 3-(phenylsulfonyl)-5-piperazin-1-yl-1H-pyrrolo[2,3-b]pyridine;

[0071]3[-(3-cyanophenyl)sulfonyl]-5-piperazin-1-yl-1H-pyrrolo[2,3-b]pyridine;

[0072]5-(4-benzylpiperazin-1-yl)-3-[(1-naphthyl)sulfonyl]-1H-pyrrolo[3,2-c]pyridine;

[0073]5-(4-methylpiperazin-1-yl)-3-[(2-naphthyl)sulfonyl]-1H-pyrrolo[3,2-b]pyridine;

[0074]3-[(2-chloro-4-fluorophenyl)sulfonyl]-5-(4-propylpiperazin-1-yl)-1H-pyrrolo[2,3-b]pyridine;

[0075]1-methyl-3-(phenylsulfonyl)-5-piperazin-1-yl-1H-pyrrolo[3,2-b]pyridine;

[0076]1-phenyl-3-(phenylsulfonyl)-5-piperazin-1-yl-1H-pyrrolo[2,3-c]pyridine;

[0077]5-(4-benzylpiperazin-1-yl)-3-[(3-fluorophenyl)sulfonyl]-1H-pyrrolo[3,2-c]pyridine;

[0078]3-[(4-fluorophenyl)sulfonyl]-5-(4-methylpiperazin-1-yl)-1H-pyrrolo[3,2-b]pyridine;

[0079]3-[(2-chlorophenyl)sulfonyl]-5-(4-propylpiperazin-1-yl)-1H-pyrrolo[2,3-b]pyridine;

[0080]3-[(4-aminophenyl)sulfonyl]-5-piperazin-1-yl-1H-pyrrolo[2,3-b]pyridine;

[0081]2-methyl-3-(phenylsulfonyl)-5-piperazin-1-yl-1H-pyrrolo[2,3-b]pyridine;

[0082]4-chloro-3-(phenylsulfonyl)-5-piperazin-1-yl-1H-pyrrolo[2,3-b]pyridine;

[0083]7-fluoro-3-(phenylsulfonyl)-5-piperazin-1-yl-1H-pyrrolo[2,3-b]pyridine;

[0084]6-fluoro-3-(phenylsulfonyl)-5-piperazin-1-yl-1H-pyrrolo[2,3-c]pyridine;

[0085]6-(4-benzylpiperazin-1-yl)-3-(phenylsulfonyl)-1H-pyrrolo[3,2-c]pyridine;

[0086]6-(4-methylpiperazin-1-yl)-3-(phenylsulfonyl)-1H-pyrrolo[3,2-b]pyridine;

[0087]3-(phenylsulfonyl)-6-(4-propylpiperazin-1-yl)-1H-pyrrolo[2,3-b]pyridine;

[0088] 3-(phenylsulfonyl)-6-piperazin-1-yl-1H-pyrrolo[2,3-b]pyridine;

[0089]4-(4-benzylpiperazin-1-yl)-3-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine;

[0090]4-(4-methylpiperazin-1-yl)-3-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine;

[0091]3-(phenylsulfonyl)-4-(4-propylpiperazin-1-yl)-1H-pyrrolo[3,2-c]pyridine;

[0092] 3-(phenylsulfonyl)-4-piperazin-1-yl-1H-pyrrolo[3,2-b]pyridine;

[0093] 3-(phenylsulfonyl)-7-piperazin-1-yl-1H-pyrazolo[4,3-b]pyridine;

[0094]3-[(1-naphthyl)sulfonyl]-5-piperazin-1-yl-1H-pyrazolo[4,3-b]pyridine;

[0095] 3-(phenylsulfonyl)-5-piperazin-1-yl-1H-pyrazolo[4,3-b]pyridine;

[0096]3-[(3-fluorophenyl)sulfonyl]-5-piperazin-1-yl-1H-pyrazolo[4,3-b]pyridine;

[0097]3-[(3-fluorophenyl)sulfonyl]-7-piperazin-1-yl-1H-pyrazolo[4,3-b]pyridine;

[0098] 3-(phenylsulfonyl)-7-piperazin-1-yl-1H-pyrazolo[3,4-c]pyridine;

[0099]3-[(1-naphthyl)sulfonyl]-7-piperazin-1-yl-1H-pyrazolo[3,4-c]pyridine;

[0100]3-(2-thienylsulfonyl)-7-piperazin-1-yl-1H-pyrazolo[3,4-c]pyridine;

[0101]3-[(3-fluorophenyl)sulfonyl]-1-methyl-7-piperazin-1-yl-1H-pyrazolo[3,4-c]pyridine;

[0102]3-[(3-fluorophenyl)sulfonyl]-7-piperazin-1-yl-1H-pyrazolo[3,4-c]pyridine;

[0103] 3-(phenylsulfonyl)-5-piperazin-1-yl-1H-pyrazolo[3,4-c]pyridine;

[0104]3-[(1-naphthyl)sulfonyl]-5-piperazin-1-yl-1H-pyrazolo[3,4-c]pyridine;

[0105] 3-(phenylsulfonyl)-7-piperazin-1-yl-1H-pyrazolo[4,3-c]pyridine;

[0106]3-[(1-naphthyl)sulfonyl]-7-piperazin-1-yl-1H-pyrazolo[4,3-c]pyridine;

[0107]3-(2-thienylsulfonyl)-7-piperazin-1-yl-1H-pyrazolo[4,3-c]pyridine;

[0108]3-[(3-fluorophenyl)sulfonyl]-1-methyl-7-piperazin-1-yl-1H-pyrazolo[4,3-c]pyridine;

[0109]3-[(3-fluorophenyl)sulfonyl]-7-piperazin-1-yl-1H-pyrazolo[4,3-c]pyridine;

[0110] 3-(phenylsulfonyl)-5-piperazin-1-yl-1H-pyrazolo[3,4-b]pyridine;

[0111]3-[(1-naphthyl)sulfonyl]-5-piperazin-1-yl-1H-pyrazolo[3,4-b]pyridine;

[0112]3-(2-thienylsulfonyl)-5-piperazin-1-yl-1H-pyrazolo[3,4-b]pyridine;

[0113]3-[(3-fluorophenyl)sulfonyl]-1-methyl-5-piperazin-1-yl-1H-pyrazolo[3,4-b]pyridine;

[0114]3-[(3-fluorophenyl)sulfonyl]-5-piperazin-1-yl-1H-pyrazolo[3,4-b]pyridine;

[0115] the stereoisomers thereof; or the pharmaceutically acceptablesalts thereof.

[0116] Compounds of the invention may be prepared using conventionalsynthetic methods and, if required, standard separation or isolationtechniques. For example, compounds of formula I wherein R₃ is H and W isCR₂ (Ia) may be prepared by reacting a nitropyridine compound of formulaII with reducing agents such as Fe, Zn or Sn in the presence of an acidto give the amine of formula III; reacting said amine with anappropriate orthoester of formula IV to give the formula V compound; andcyclizing the formula V compound in the presence of a base to give thedesired azaindole product of formula Ia. Methods known to prepare3-sulfonylazaindoles are described by Wojciechowski, K. and Makosza, M.,Synthesis 1986, 651-653 and by Orlemans, E. O. M.; Schreuder, A. H.;Conti, P. G. M.; Verboom, W.; and Reinhoudt, D. N., Tetrahedron 1987,43, 3817-3826. In a similar manner, the formula III amine may be reactedwith NaNO₂ in the presence of an acid to give those compounds of formulaI wherein R₃ is H and W is N (Ib). The reactions are shown in flowdiagram I.

[0117] Compounds of formula II wherein Z is N; Y is CR₅ and R₅ is agroup M (IIa) may be prepared by reacting a nitropyridine of formula VIwith a diazacyclic compound of formula VII in the presence of a basesuch as K₂CO₃ to give the formula IIa compound. The formula IIa compoundmay then be reduced and cyclized as described hereinabove in flowdiagram I to give compounds of formula I wherein Z is N; Y is CR₅; andR₅ is a group M (Ic). The reactions are shown in flow diagram II whereinHal represents chlorine, bromine or fluorine.

[0118] Alternatively, compounds of formula Ic may be prepared directlyfrom an azaindole or azaindazole compound of formula VIII by couplingthe formula VIII substrate with a diazacyclic compound of formula VII inthe presence of a catalyst, such as a palladium catalyst, to give theprotected compound of formula IX and deprotecting the formula IXcompound to give the desired compound of formula Ic. The reaction isshown in flow diagram III wherein LG represents a leaving group such asiodine, bromine, chlorine or an activated hydroxyl group, for example atriflate (CF₃SO₃) and P is a protecting group.

[0119] Compounds of formula VIII, or the isosteres or regisomersthereof, may be prepared by conventional methods. For example, aprotected azaindole or azaindazole of formula X may be reacted with amethylsulfonyl compound of formula XI to give the 3-thio compound offormula XII; said 3-thio compound may be oxidized using a conventionaloxidizing agent such as H₂O₂, m-chloroperbenzoic acid or the like togive the corresponding 3-sulfonyl compound of formula VIII. The reactionis shown in flow diagram IV wherein LG and P are as describedhereinabove.

[0120] Compounds of formula Ib or Ic wherein R₃ is other than H may beprepared using conventional alkylation/deprotection or couplingprocedures, such as a Suzuki-type coupling. For example, compounds offormula I wherein Y is N; Z is CR₆; R₆ is a group M; and R₃ is otherthan H (Id) may be prepared by reacting a protected compound of formulaXIII with an alkylating agent of formula XIV in the presence of a baseand a solvent optionally in the presence of a phase-transfer agent togive the protected alkylated compound of formula XV and deprotectingsaid formula XV compound to give the desired compound of formula Idwherein R₁₇ is H; optionally this compound may be reacted with analkylating agent of formula XVI under standard alkylation conditions togive the compound of formula Id wherein R₁₇ is other than H. If desired,the sequence may be reversed by deprotecting the formula XIV compound togive the compound of formula I wherein R₃ and R₁₇ are H (Ie) andalkylating the formula Ie compound with the formula XVI alkylating agentto give the compound of formula Id. The reactions are shown in flowdiagram V wherein P is a protecting group and LG′ is a leaving groupsuch as Cl, Br, I, OH, tosyl, mesyl or the like.

[0121] It is understood that the reaction sequences shown in flowdiagrams II, III, IV and V are applicable to the corresponding isostereswherein any one of X, Y, Z or Q may represent N or to the correspondingregio isomers wherein any one of R₄, R₅, R₆ or R₇ may represent a groupM.

[0122] Protecting groups suitable for use in the reactions shownhereinabove include t-butyloxycarbonyl, benzyl, acetyl,benzyloxycarbonyl, or any conventional group known to protect a basicnitrogen in standard synthetic procedures.

[0123] Advantageously, the formula I compounds of the invention areuseful for the treatment of CNS disorders related to or affected by the5-HT6 receptor, including motor, mood, personality, behavioral,psychiatric, cognitive, neurodegenerative, or the like disorders, forexample Alzheimer's disease, Parkinson's disease, attention deficitdisorder, anxiety, epilepsy, depression, obsessive compulsive disorder,sleep disorders, neurodegenerative disorders (such as head trauma orstroke), feeding disorders (such as anorexia or bulimia), schizophrenia,memory loss, disorders associated with withdrawal from drug or nicotineabuse, or the like or certain gastrointestinal disorders such asirritable bowel syndrome. Accordingly, the present invention provides amethod for the treatment of a disorder of the central nervous systemrelated to or affected by the 5-HT6 receptor in a patient in needthereof which comprises providing said patient a therapeuticallyeffective amount of a compound of formula I as described hereinabove.The compounds may be provided by oral or parenteral administration or inany common manner known to be an effective administration of atherapeutic agent to a patient in need thereof.

[0124] The term “providing” as used herein with respect to providing acompound or substance embraced by the invention, designates eitherdirectly administering such a compound or substance, or administering aprodrug, derivative or analog which forms an equivalent amount of thecompound or substance within the body.

[0125] The therapeutically effective amount provided in the treatment ofa specific CNS disorder may vary according to the specific condition(s)being treated, the size, age and response pattern of the patient, theseverity of the disorder, the judgment of the attending physician andthe like. In general, effective amounts for daily oral administrationmay be about 0.01 to 1,000 mg/kg, preferably about 0.5 to 500 mg/kg andeffective amounts for parenteral administration may be about 0.1 to 100mg/kg, preferably about 0.5 to 50 mg/kg.

[0126] In actual practice, the compounds of the invention are providedby administering the compound or a precursor thereof in a solid orliquid form, either neat or in combination with one or more conventionalpharmaceutical carriers or excipients. Accordingly, the presentinvention provides a pharmaceutical composition which comprises apharmaceutically acceptable carrier and an effective amount of acompound of formula I as described hereinabove.

[0127] Solid carriers suitable for use in the composition of theinvention include one or more substances which may also act as flavoringagents, lubricants, solubilizers, suspending agents, fillers, glidants,compression aides, binders, tablet-disintegrating agents orencapsulating materials. In powders, the carrier may be a finely dividedsolid which is in admixture with a finely divided compound of formula I.In tablets, the formula I compound may be mixed with a carrier havingthe necessary compression properties in suitable proportions andcompacted in the shape and size desired. Said powders and tablets maycontain up to 99% by weight of the formula I compound. Solid carrierssuitable for use in the composition of the invention include calciumphosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch,gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose,polyvinylpyrrolidine, low melting waxes and ion exchange resins.

[0128] Any pharmaceutically acceptable liquid carrier suitable forpreparing solutions, suspensions, emulsions, syrups and elixirs may beemployed in the composition of the invention. Compounds of formula I maybe dissolved or suspended in a pharmaceutically acceptable liquidcarrier such as water, an organic solvent, or a pharmaceuticallyacceptable oil or fat, or a mixture thereof. Said liquid composition maycontain other suitable pharmaceutical additives such as solubilizers,emulsifiers, buffers, preservatives, sweeteners, flavoring agents,suspending agents, thickening agents, coloring agents, viscosityregulators, stabilizers, osmo-regulators, or the like. Examples ofliquid carriers suitable for oral and parenteral administration includewater (particularly containing additives as above, e.g., cellulosederivatives, preferably sodium carboxymethyl cellulose solution),alcohols (including monohydric alcohols and polyhydric alcohols, e.g.,glycols) or their derivatives, or oils (e.g., fractionated coconut oiland arachis oil). For parenteral administration the carrier may also bean oily ester such as ethyl oleate or isopropyl myristate.

[0129] Compositions of the invention which are sterile solutions orsuspensions are suitable for intramuscular, intraperitoneal orsubcutaneous injection. Sterile solutions may also be administeredintravenously. Inventive compositions suitable for oral administrationmay be in either liquid or solid composition form.

[0130] For a more clear understanding, and in order to illustrate theinvention more clearly, specific examples thereof are set forthhereinbelow. The following examples are merely illustrative and are notto be understood as limiting the scope and underlying principles of theinvention in any way.

[0131] The term NMR designates proton nuclear magnetic resonance. Theterms DMF and EtOAc designate dimethyl formamide and ethyl acetate,respectively. The term THF designates tetrahydrofuran. In thestructures, the term Ph designates a phenyl group.

EXAMPLE 1 Preparation of 1-Methyl-4-(5-nitropyridin-2-yl)piperazine

[0132]

[0133] A stirred mixture of 2-chloro-5-nitropyridine (3.16 g, 20.0mmol), 1-methyl-piperazine (2.00 g, 2.00 mmol) and potassium carbonate(2.76 g, 20.0 mmol) in DMF is heated at 100° C. for 24 h, cooled, pouredinto water and extracted with CH₂Cl₂. The combined extracts are driedover MgSO₄ and concentrated in vacuo. The resultant residue is purifiedby flash chromatography (SiO₂, 2% ammonia in 10:90 ethanol:ethyl acetateas eluent) affords the title compound as an off-white solid, 4.0 g (90%yield), identified by NMR analysis.

EXAMPLE 2 Preparation of1-Methyl-4-{5-nitro-6-[(phenylsulfonyl)methyl]pyridin-2-yl}piperazine

[0134]

[0135] A stirred solution of 1-methyl-4-(5-nitropyridin-2-yl)piperazine(1.10 g, 5.00 mmol) and chloromethylphenylsulfone (0.950 g, 5.00 mmol)in dry THF, under nitrogen, is cooled to −60° C., treated with 1.0 MKO^(t)Bu in THF (10.0 mL, 10.0 mmol), allowed to warm to −10° C. over a1 h period, quenched with acetic acid, treated sequentially with waterand saturated aqueous NaHCO₃ and extracted with CH₂Cl₂. The combinedextracts are washed sequentially with water and brine, dried over MgSO₄and concentrated in vacuo. The resultant residue is crystallized fromEtOAc to give the title compound as a yellow solid, 1.60 g (85% yield),mp: 170°-172° C., identified by mass spectral and NMR analyses.

EXAMPLE 3 Preparation of6-(4-Methylpiperazin-1-yl)-2-[(phenyisulfonyl)methyl]pyridin-3-yl-amine

[0136]

[0137] A mixture of1-methyl-4-{5-nitro-6-[(phenylsulfonyl)methyl]pyridin-2-yl}-piperazine(1.60 g, 4.35 mmol) and 10% Pd/C (200 mg) in a 1:1 mixture ofethanol:THF is hydrogenated at 45 psi for 4 h at ambient temperatures.The catalyst is filtered off and the filtrate is concentrated in vacuoto afford the title compound as a yellow solid, 1.45 g (99% yield),identified by NMR analysis.

EXAMPLE 4 Preparation of5-(4-methylpiperazin-1-yl)-3-(phenyisulfonyl)-1H-pyrazolo-[4,3-b]pyridinehydrochloride

[0138]

[0139] A stirred solution of2-[(phenylsulfonyl)methyl]-6-(4-methylpiperazin-1-yl)-pyridin-3-ylamine(1.20 g, 3.50 mmol) in 1.0 M aqueous hydrochloric acid (20 mL) is cooledin an ice bath, treated dropwise with NaNO₂ (358 mg, 5.2 mmol) in water,stirred for 1 h, treated with aqueous saturated NaHCO₃ and filtered. Thebrown solid filtercake is washed with water, dried in vacuo, trituratedwith acetone and filtered. The filtercake is washed with ether andair-dried to afford the free amine of the title compound as a tan solid,0.50 g. This solid is dissolved in a mixture of ethanol and 4.0 M HCl indioxane and concentrated in vacuo. The resultant residue is trituratedwith ether to afford the title compound as an off-white solid, mp>250°C., identified by mass spectral and NMR analyses.

EXAMPLE 5 Preparation of2-Chloro-5-nitro-6-[(phenyisulfonyl)methyl]pyridine (A) and2-Chloro-5-nitro-4-[(phenyisulfonyl)methyl]pyridine (B)

[0140]

[0141] A stirred solution of 2-chloro-5-nitro-pyridine (3.97 g, 25.0mmol) and chloromethylphenylsulfone (4.76 g, 25.0 mmol) in dry THF at−65° C. under nitrogen is treated with 1.0M KO-t-Bu in THF (55.0 mL,55.0 mmol), allowed to warm to 0° C. over 1.5 h, treated with glacialacetic acid (5.5 mL), stirred for 0.5 h, treated with saturated aqueousNaHCO₃, stirred for 2 h, and extracted with CH₂Cl₂. The combinedextracts are washed with brine, dried over MgSO₄ and concentrated invacuo to afford a brown oil. The oil is chromatographed (silica gel,50:50 EtOAc:hexanes as eluent) to give a slightly yellow solididentified by NMR as a mixture of the two title regioisomers A and B(5.67 g, 73%). A second chromatography (silica gel, 40:60 EtOAc:hexanesas eluent) provides the title compound A as a white solid, 1.75 g (23%yield), identified by NMR and mass spectral analyses and the titlecompound B as a white solid, 0.79 g (10% yield), identified by NMR andmass spectral analyses.

EXAMPLE 6 Preparation of6-(4-Benzylpiperazin-1-yl)-3-nitro-2-[(phenylsulfonyl)methyl]-pyridine

[0142]

[0143] A stirred mixture of2-chloro-5-nitro-6-[(phenylsulfonyl)methyl]pyridine (1.41 g, 4.50 mmol),1-benzylpiperazine (0.873 g, 4.95 mmol), and K₂CO₃ (0.683 g, 4.95 mmol)in ethanol is heated at reflux temperature for 1.5 h, cooled, dilutedwith water and extracted with CH₂Cl₂. The extracts are combined, driedover MgSO₄ and concentrated in vacuo. The resultant residue ischromatographed (silica gel, EtOAc as eluent) to afford the titlecompound as an orange-yellow solid, 1.96 g (96% yield), mp 175-176° C.,identified by NMR and mass spectral analyses.

EXAMPLE 7 Preparation of3-Amino-6-(4-benzylpiperazin-1-yl)-2-[(phenyisulfonyl)methyl]-pyridine

[0144]

[0145] A stirred mixture of6-(4-benzylpiperazin-1-yl)-3-nitro-2-[(phenylsulfonyl)-methyl]pyridine(1.81 g, 4.00 mmol) and granular tin (2.09 g, 17.6 mmol) in methanol istreated with conc. HCl, heated under nitrogen at 50° C. for 7 h ,stirred at ambient temperatures for 16 h, poured into aqueous NaHCO₃ andextracted with EtOAc. The combined extracts are dried over MgSO₄ andconcentrated in vacuo. The resultant residue is chromatographed (silicagel, EtOAc as eluent) to afford the title compound as a yellow solid,1.47 g (87% yield), mp 175-176° C., identified by NMR and mass spectralanalyses.

EXAMPLE 8 Preparation of5-(4-Benzylpiperazin-1-yl)-3-(phenyisulfonyl)-1H-pyrrolo[3,2-b]pyridine

[0146]

[0147] A stirred solution of3-amino-6-(4-benzylpiperazin-1-yl)-2-[(phenylsulfonyl)-methyl]pyridine(1.41 g, 3.34 mmol), p-toluenesulfonic acid monohydrate (63 mg, 0.33mmol), triethyl orthoformate (2.78 mL, 16.7 mmol) in 1,2-dichloroethaneis heated at reflux temperature under nitrogen for 7.5 h, stirred atroom temperature for 16 h and in vacuo to afford an oil residue. Theresidue is stirred in dry THF, treated with 1.0M KO-t-Bu in THF (4.35mL, 4.35 mmol) for 2 h, treated sequentially with saturated aqueousNH₄Cl , saturated aqueous NaHCO₃ and water and extracted with CH₂Cl₂.The combined extracts are dried over MgSO₄ and concentrated in vacuo togive a yellow solid residue. This residue is chromatograped (silica gel,EtOAc as eluent to afford the title compound as a pale yellow solid,1.18 g (79% yield), mp 238-239° C., identified by NMR and mass spectralanalyses.

EXAMPLE 9 Preparation3-(Phenyisulfonyl)-5-piperazin-1-yl-1H-pyrrolo[3,2-b]pyridineDihydrochloride

[0148]

[0149] A stirred mixture of5-(4-benzylpiperazin-1-yl)-3-(phenylsulfonyl)-1H-pyrrolo[3,2-b]pyridine(0.865 g, 2.00 mmol) and 1-chloroethylchloroformate (0.65 mL, 6.00 mmol)in 1,2-dichloroethane is heated at reflux temperature for 2.5 h undernitrogen, cooled and concentrated in vacuo, and reconcentrated fromCH₂Cl₂ to a solid. This solid is heated with ethanol at refluxtemperature under nitrogen for 2 h, cooled and concentrated in vacuo.The resultant residue is stirred in ethanol for 16 h and filtered. Thefiltercake is heated with methanol and two drops of concentratedhydrochloric acid for 30 h and concentrated in vacuo to a solid. Thissolid is chromatographed (silica gel, 5:95 concentrated ammoniumhydroxide:ethanol as eluent) to afford the free amine of the titlecompound as a white solid. The free amine is dissolved in methanol,treated with 2.0 M aqueous hydrochloric acid (1.1 mL, 2.2 mmol) andconcentrated to an off-white solid residue. This residue isrecystallized from methanol to afford the title compound as an off-whitesolid, 165 mg (24% yield), mp 198-203° C. (foams), identified by NMR andmass spectral analyses.

EXAMPLE 10 Comparative Evaluation of 5-HT6 Binding Affinity of TestCompounds

[0150] The affinity of test compounds for the serotonin 5-HT6 receptoris evaluated in the following manner. Cultured Hela cells expressinghuman cloned 5-HT6 receptors are harvested and centrifuged at low speed(1,000×g) for 10.0 min to remove the culture media. The harvested cellsare suspended in half volume of fresh physiological phosphate bufferedsaline solution and recentrifuged at the same speed. This operation isrepeated. The collected cells are then homogenized in ten volumes of 50mM Tris.HCl (pH 7.4) and 0.5 mM EDTA. The homogenate is centrifuged at40,000×g for 30.0 min and the precipitate is collected. The obtainedpellet is resuspended in 10 volumes of Tris.HCl buffer and recentrifugedat the same speed. The final pellet is suspended in a small volume ofTris.HCl buffer and the tissue protein content is determined in aliquotsof 10-25 μl volumes. Bovine Serum Albumin is used as the standard in theprotein determination according to the method described in Lowry et al.,J. Biol. Chem., 193:265 (1951). The volume of the suspended cellmembranes is adjusted to give a tissue protein concentration of 1.0mg/ml of suspension. The prepared membrane suspension (10 timesconcentrated) is aliquoted in 1.0 ml volumes and stored at −70° C. untilused in subsequent binding experiments.

[0151] Binding experiments are performed in a 96 well microtiter plateformat, in a total volume of 200 μl. To each well is added the followingmixture: 80.0 ∞l of incubation buffer made in 50 mM Tris.HCl buffer (pH7.4) containing 10.0 mM MgCl₂ and 0.5 mM EDTA and 20 μl of [³H]-LSD(S.A., 86.0 Ci/mmol, available from Amersham Life Science), 3.0 nM. Thedissociation constant, K_(D) of the [³H]LSD at the human serotonin 5-HT6receptor is 2.9 nM, as determined by saturation binding with increasingconcentrations of [³H]LSD. The reaction is initiated by the finaladdition of 100.0 μl of tissue suspension. Nonspecific binding ismeasured in the presence of 10.0 μM methiothepin. The test compounds areadded in 20.0 μl volume.

[0152] The reaction is allowed to proceed in the dark for 120 min atroom temperature, at which time, the bound ligand-receptor complex isfiltered off on a 96 well unifilter with a Packard Filtermate® 196Harvester. The bound complex caught on the filter disk is allowed to airdry and the radioactivity is measured in a Packard TopCount® equippedwith six photomultiplier detectors, after the addition of 40.0 μlMicroscint®−20 scintillant to each shallow well. The unifilter plate isheat-sealed and counted in a PackardTopCount® with a tritium efficiencyof 31.0%.

[0153] Specific binding to the 5-HT6 receptor is defined as the totalradioactivity bound less the amount bound in the presence of 10.0 μMunlabeled methiothepin. Binding in the presence of varyingconcentrations of test compound is expressed as a percentage of specificbinding in the absence of test compound. The results are plotted as log% bound versus log concentration of test compound. Nonlinear regressionanalysis of data points with a computer assisted program Prism® yieldedboth the IC₅₀ and the K_(i) values of test compounds with 95% confidencelimits. A linear regression line of data points is plotted, from whichthe IC₅₀ value is determined and the K_(i) value is determined basedupon the following equation:

K_(i)=IC₅₀/(1+L/K_(D))

[0154] where L is the concentration of the radioactive ligand used andK_(D) is the dissociation constant of the ligand for the receptor, bothexpressed in nM.

[0155] Using this assay, the following Ki values are determined andcompared to those values obtained by representative compounds known todemonstrate binding to the 5-HT6 receptor. The data are shown in TableI, below. TABLE I 5-HT6 Binding Ki (nM) Test Compound (Ex. No.) 4 34 830 9 2 Comparative Examples Loxapine 41.4 Mianserin 44.2

What is claimed is:
 1. A compound of formula I

wherein W is N or CR₂; X is N or CR₄; Y is N or CR₅; Z is N or CR₆; Q isN or CR₇ with the proviso that at least one and not more than two of X,Y, Z and Q must be N; R₁ is an optionally substituted C₁-C₆alkyl,C₃-C₇cycloalkyl, aryl, or heteroaryl group or an optionally substituted8- to 13-membered bicyclic or tricyclic ring system having a N atom atthe bridgehead and optionally containing 1, 2 or 3 additionalheteroatoms selected from N, O or S; R₂ is H, halogen, or a C₁-C₆alkyl,C₁-C₆alkoxy, C₃-C₇cycloalkyl, aryl or heteroaryl group each optionallysubstituted; R₃ is H or a C₁-C₆alkyl, C₃-C₇cycloalkyl, aryl orheteroaryl group each optionally substituted; R₄, R₅, R₆ and R₇ are eachindependently H, halogen, CN, COR₈, OCO₂R₉, CO₂R₁₀, CONR₁₁R₁₂,SO_(n)R₁₃, NR₁₄R₁₅, OR₁₆ or a C₁-C₆alkyl, C₃-C₇cycloalkyl, aryl orheteroaryl group each optionally substituted or a group M having thestructure

 with the proviso that at least one of R₄, R₅, R₆ or R₇ must be a groupM and with the further proviso that when W is CR₂ and X or Z is N, thenR₇ must be other than a group M; R₈, R₉, R₁₀ and R₁₃ are eachindependently H or a C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,C₃-C₆cycloalkyl, cycloheteroalkyl, aryl or heteroaryl group eachoptionally substituted; R₁₁, R₁₂, R₁₄ and R₁₅ are each independently Hor an optionally substituted C₁-C₄alkyl group or R₁₁ and R₁₂ or R₁₄ andR₁₅ may be taken together with the atom to which they are attached toform a 5- to 7-membered ring optionally containing another heteroatomselected from O, NR₂₂ or SO_(n); R₁₆ is H or a C₁-C₆alkyl, C₂-C₆alkenyl,C₂-C₆alkynyl, C₃-C₇cycloalkyl, cycloheteroalkyl, aryl or heteroarylgroup each optionally substituted; n is 0 or an integer of 1 or 2; R₁₇is H or a C₁-C₆alkyl or C₃-C₇cycloalkyl group each optionallysubstituted; R₁₈, R₁₉, R₂₀, R₂₁ and R₂₃ are each independently H or aC₁-C₆alkyl or C₃-C₇cycloalkyl group each optionally substituted; m is 1or 2; and R₂₂ is H or a C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,C₃-C₇cycloalkyl, cycloheteroalkyl, aryl or heteroaryl group eachoptionally substituted; or the stereoisomers thereof or thepharmaceutically acceptable salts thereof.
 2. The compound according toclaim 1 wherein m is
 1. 3. The compound according to claim 1 wherein Yis CR₅ and R₅ is a group M.
 4. The compound according to claim 1 whereinW is N; Q is CR₇; and R₇ is a group M.
 5. The compound according toclaim 2 wherein wherein Y is CR₅ and R₅ is a group M.
 6. The compoundaccording to claim 2 wherein W is N; Q is CR₇; and R₇ is a group M 7.The compound according to claim 2 wherein R₁ is an optionallysubstituted phenyl, naphthyl or heteroaryl group
 8. The compoundaccording to claim 7 wherein R₅ or R₇ is a group M.
 9. The compoundaccording to claim 1 selected from the group consisting of:5-(4-benzylpiperazin-1-yl)-3-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine;5-(4-methylpiperazin-1-yl)-3-(phenylsulfonyl)-1H-pyrrolo[2,3-c]pyridine;3-(phenylsulfonyl)-5-(4-propylpiperazin-1-yl)-1H-pyrrolo[2,3-b]pyridine;3-(phenylsulfonyl)-5-piperazin-1-yl-1H-pyrrolo[2,3-b]pyridine;3[-(3-cyanophenyl)sulfonyl]-5-piperazin-1-yl-1H-pyrrolo[2,3-b]pyridine;5-(4-benzylpiperazin-1-yl)-3-[(1-naphthyl)sulfonyl]-1H-pyrrolo[3,2-c]pyridine;5-(4-methylpiperazin-1-yl)-3-[(2-naphthyl)sulfonyl]-1H-pyrrolo[3,2-b]pyridine;3-[(2-chloro-4-fluorophenyl)sulfonyl]-5-(4-propylpiperazin-1-yl)-1H-pyrrolo[2,3-b]pyridine;1-methyl-3-(phenylsulfonyl)-5-piperazin-1-yl-1H-pyrrolo[3,2-b]pyridine;1-phenyl-3-(phenylsulfonyl)-5-piperazin-1-yl-1H-pyrrolo[2,3-c]pyridine;5-(4-benzylpiperazin-1-yl)-3-[(3-fluorophenyl)sulfonyl]-1H-pyrrolo[3,2-c]pyridine;3-[(4-fluorophenyl)sulfonyl]-5-(4-methylpiperazin-1-yl)-1H-pyrrolo[3,2-b]pyridine;3-[(2-chlorophenyl)sulfonyl]-5-(4-propylpiperazin-1-yl)-1H-pyrrolo[2,3-b]pyridine;3-[(4-aminophenyl)sulfonyl]-5-piperazin-1-yl-1H-pyrrolo[2,3-b]pyridine;2-methyl-3-(phenylsulfonyl)-5-piperazin-1-yl-1H-pyrrolo[2,3-b]pyridine;4-chloro-3-(phenylsulfonyl)-5-piperazin-1-yl-1H-pyrrolo[2,3-b]pyridine;7-fluoro-3-(phenylsulfonyl)-5-piperazin-1-yl-1H-pyrrolo[2,3-b]pyridine;6-fluoro-3-(phenylsulfonyl)-5-piperazin-1-yl-1H-pyrrolo[2,3-c]pyridine;6-(4-benzylpiperazin-1-yl)-3-(phenylsulfonyl)-1H-pyrrolo[3,2-c]pyridine;6-(4-methylpiperazin-1-yl)-3-(phenylsulfonyl)-1H-pyrrolo[3,2-b]pyridine;3-(phenylsulfonyl)-6-(4-propylpiperazin-1-yl)-1H-pyrrolo[2,3-b]pyridine;3-(phenylsulfonyl)-6-piperazin-1-yl-1H-pyrrolo[2,3-b]pyridine;4-(4-benzylpiperazin-1-yl)-3-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine;4-(4-methylpiperazin-1-yl)-3-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine;3-(phenylsulfonyl)-4-(4-propylpiperazin-1-yl)-1H-pyrrolo[3,2-c]pyridine;3-(phenylsulfonyl)-4-piperazin-1-yl-1H-pyrrolo[3,2-b]pyridine;3-(phenylsulfonyl)-7-piperazin-1-yl-1H-pyrazolo[4,3-b]pyridine;3-[(1-naphthyl)sulfonyl]-5-piperazin-1-yl-1H-pyrazolo[4,3-b]pyridine;3-(phenylsulfonyl)-5-piperazin-1-yl-1H-pyrazolo[4,3-b]pyridine;3-[(3-fluorophenyl)sulfonyl]-5-piperazin-1-yl-1H-pyrazolo[4,3-b]pyridine;3-[(3-fluorophenyl)sulfonyl]-7-piperazin-1-yl-1H-pyrazolo[4,3-b]pyridine;3-(phenylsulfonyl)-7-piperazin-1-yl-1H-pyrazolo[3,4-c]pyridine;3-[(1-naphthyl)sulfonyl]-7-piperazin-1-yl-1H-pyrazolo[3,4-c]pyridine;3-(2-thienylsulfonyl)-7-piperazin-1-yl-1H-pyrazolo[3,4-c]pyridine;3-[(3-fluorophenyl)sulfonyl]-1-methyl-7-piperazin-1-yl-1H-pyrazolo[3,4-c]pyridine;3-[(3-fluorophenyl)sulfonyl]-7-piperazin-1-yl-1H-pyrazolo[3,4-c]pyridine;3-(phenylsulfonyl)-5-piperazin-1-yl-1H-pyrazolo[3,4-c]pyridine;3-[(1-naphthyl)sulfonyl]-5-piperazin-1-yl-1H-pyrazolo[3,4-c]pyridine;3-(phenylsulfonyl)-7-piperazin-1-yl-1H-pyrazolo[4,3-c]pyridine;3-[(1-naphthyl)sulfonyl]-7-piperazin-1-yl-1H-pyrazolo[4,3-c]pyridine;3-(2-thienylsulfonyl)-7-piperazin-1-yl-1H-pyrazolo[4,3-c]pyridine;3-[(3-fluorophenyl)sulfonyl]-1-methyl-7-piperazin-1-yl-1H-pyrazolo[4,3-c]pyridine;3-[(3-fluorophenyl)sulfonyl]-7-piperazin-1-yl-1H-pyrazolo[4,3-c]pyridine;3-(phenylsulfonyl)-5-piperazin-1-yl-1H-pyrazolo[3,4-b]pyridine;3-[(1-naphthyl)sulfonyl]-5-piperazin-1-yl-1H-pyrazolo[3,4-b]pyridine;3-(2-thienylsulfonyl)-5-piperazin-1-yl-1H-pyrazolo[3,4-b]pyridine;3-[(3-fluorophenyl)sulfonyl]-1-methyl-5-piperazin-1-yl-1H-pyrazolo[3,4-b]pyridine;3-[(3-fluorophenyl)sulfonyl]-5-piperazin-1-yl-1H-pyrazolo[3,4-b]pyridine;a stereoisomer thereof; and a pharmaceutically acceptable salt thereof.10. A method for the treatment of a central nervous system disorderrelated to or affected by the 5-HT6 receptor in a patient in needthereof which comprises providing to said patient a therapeuticallyeffective amount of a compound of formula I

wherein W is N or CR₂; X is N or CR₄; Y is N or CR₅; Z is N or CR₆; Q isN or CR₇ with the proviso that at least one and not more than two of X,Y, Z and Q must be N; R₁ is an optionally substituted C₁-C₆alkyl,C₃-C₇cycloalkyl, aryl, or heteroaryl group or an optionally substituted8- to 13-membered bicyclic or tricyclic ring system having a N atom atthe bridgehead and optionally containing 1, 2 or 3 additionalheteroatoms selected from N, O or S; R₂ is H, halogen, or a C₁-C₆alkyl,C₁-C₆alkoxy, C₃-C₇cycloalkyl, aryl or heteroaryl group each optionallysubstituted; R₃ is H or a C₁-C₆alkyl, C₃-C₇cycloalkyl, aryl orheteroaryl group each optionally substituted; R₄, R₅, R₆ and R₇ are eachindependently H, halogen, CN, COR₈, OCO₂R₉, CO₂R₁₀, CONR₁₁R₁₂,SO_(n)R₁₃, NR₁₄R₁₅, OR₁₆ or a C₁-C₆alkyl, C₃-C₇cycloalkyl, aryl orheteroaryl group each optionally substituted or a group M having thestructure

 with the proviso that at least one of R₄, R₅, R₆ or R₇ must be a groupM and with the further proviso that when W is CR₂ and X or Z is N, thenR₇ must be other than a group M; R₈, R₉, R₁₀ and R₁₃ are eachindependently H or a C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,C₃-C₆cycloalkyl, cycloheteroalkyl, aryl or heteroaryl group eachoptionally substituted; R₁₁, R₁₂, R₁₄ and R₁₅ are each independently Hor an optionally substituted C₁-C₄alkyl group or R₁₁ and R₁₂ or R₁₄ andR₁₅ may be taken together with the atom to which they are attached toform a 5- to 7-membered ring optionally containing another heteroatomselected from O, NR₂₂ or SO_(n); R₁₆ is H or a C₁-C₆alkyl, C₂-C₆alkenyl,C₂-C₆alkynyl, C₃-C₇cycloalkyl, cycloheteroalkyl, aryl or heteroarylgroup each optionally substituted; n is 0 or an integer of 1 or 2; R₁₇is H or a C₁-C₆alkyl or C₃-C₇cycloalkyl group each optionallysubstituted; R₁₈, R₁₉, R₂₀, R₂₁ and R₂₃ are each independently H or aC₁-C₆alkyl or C₃-C₇cycloalkyl group each optionally substituted; m is 1or2; and R₂₂ is H or a C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,C₃-C₇cycloalkyl, cycloheteroalkyl, aryl or heteroaryl group eachoptionally substituted; or the stereoisomers thereof or thepharmaceutically acceptable salts thereof.
 11. The method according toclaim 10 wherein said disorder is a motor disorder, anxiety disorder orcognitive disorder.
 12. The method according to claim 10 wherein saiddisorder is a neurodegenerative disorder.
 13. The method according toclaim 11 wherein said disorder is selected from the group consisting of:attention deficit disorder; obsessive compulsive disorder; andwithdrawal from drug, alcohol or nicotine addiction; schizophrenia;depression; and Alzheimer's disease.
 14. The method according to claim12 wherein said disorder is selected from the group consisting ofstroke; head trauma; and neuropathic pain.
 15. A pharmaceuticalcomposition which comprises a pharmaceutically acceptable carrier and aneffective amount of a compound of formula I

wherein W is N or CR₂; X is N or CR₄; Y is N or CR₅; Z is N or CR₆; Q isN or CR₇ with the proviso that at least one and not more than two of X,Y, Z and Q must be N; R₁ is an optionally substituted C₁-C₆alkyl,C₃-C₇cycloalkyl, aryl, or heteroaryl group or an optionally substituted8- to 13-membered bicyclic or tricyclic ring system having a N atom atthe bridgehead and optionally containing 1, 2 or 3 additionalheteroatoms selected from N, O or S; R₂ is H, halogen, or a C₁-C₆alkyl,C₁-C₆alkoxy, C₃-C₇cycloalkyl, aryl or heteroaryl group each optionallysubstituted; R₃ is H or a C₁-C₆alkyl, C₃-C₇cycloalkyl, aryl orheteroaryl group each optionally substituted; R₄, R₅, R₆ and R₇ are eachindependently H, halogen, CN, COR₈, OCO₂R₉, CO₂R₁₀, CONR₁₁R₁₂,SO_(n)R₁₃, NR₁₄R₁₅, OR₁₆ or a C₁-C₆alkyl, C₃-C₇cycloalkyl, aryl orheteroaryl group each optionally substituted or a group M having thestructure

 with the proviso that at least one of R₄, R₅, R₆ or R₇ must be a groupM and with the further proviso that when W is CR₂ and X or Z is N, thenR₇ must be other than a group M; R₈, R₉, R₁₀ and R₁₃ are eachindependently H or a C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,C₃-C₆cycloalkyl, cycloheteroalkyl, aryl or heteroaryl group eachoptionally substituted; R₁₁, R₁₂, R₁₄ and R₁₅ are each independently Hor an optionally substituted C₁-C₄alkyl group or R₁₁ and R₁₂ or R₁₄ andR₁₅ may be taken together with the atom to which they are attached toform a 5- to 7-membered ring optionally containing another heteroatomselected from O, NR₂₂ or SO_(n); R₁₆ is H or a C₁-C₆alkyl, C₂-C₆alkenyl,C₂-C₆alkynyl, C₃-C₇cycloalkyl, cycloheteroalkyl, aryl or heteroarylgroup each optionally substituted; n is 0 or an integer of 1 or 2; R₁₇is H or a C₁-C₆alkyl or C₃-C₇cycloalkyl group each optionallysubstituted; R₁₈, R₁₉, R₂₀, R₂₁ and R₂₃ are each independently H or aC₁-C₆alkyl or C₃-C₇cycloalkyl group each optionally substituted; m is 1or 2; and R₂₂ is H or a C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,C₃-C₇cycloalkyl, cycloheteroalkyl, aryl or heteroaryl group eachoptionally substituted; or the stereoisomers thereof or thepharmaceutically acceptable salts thereof.
 16. The composition accordingto claim 15 having a formula I compound wherein m is
 1. 17. Thecomposition according to claim 16 having a formula I compound wherein Yis CR₅ and R₅ is a group M.
 18. The composition according to claim 16having a formula I compound wherein W is N; Q is CR₇; and R₇ is a groupM.
 19. The composition according to claim 16 having a formula I compoundwherein R₁ is an optionally substituted phenyl, naphthyl or heteroarylgroup.
 20. The composition according to claim 15 having a formula Icompound selected from the group consisting of:5-(4-benzylpiperazin-1-yl)-3-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine;5-(4-methylpiperazin-1-yl)-3-(phenylsulfonyl)-1H-pyrrolo[2,3-c]pyridine;3-(phenylsulfonyl)-5-(4-propylpiperazin-1-yl)-1H-pyrrolo[2,3-b]pyridine;3-(phenylsulfonyl)-5-piperazin-1-yl-1H-pyrrolo[2,3-b]pyridine;3[-(3-cyanophenyl)sulfonyl]-5-piperazin-1-yl-1H-pyrrolo[2,3-b]pyridine;5-(4-benzylpiperazin-1-yl)-3-[(1-naphthyl)sulfonyl]-1H-pyrrolo[3,2-c]pyridine;5-(4-methylpiperazin-1-yl)-3-[(2-naphthyl)sulfonyl]-1H-pyrrolo[3,2-b]pyridine;3-[(2-chloro-4-fluorophenyl)sulfonyl]-5-(4-propylpiperazin-1-yl)-1H-pyrrolo[2,3-b]pyridine;1-methyl-3-(phenylsulfonyl)-5-piperazin-1-yl-1H-pyrrolo[3,2-b]pyridine;1-phenyl-3-(phenylsulfonyl)-5-piperazin-1-yl-1H-pyrrolo[2,3-c]pyridine;5-(4-benzylpiperazin-1-yl)-3-[(3-fluorophenyl)sulfonyl]-1H-pyrrolo[3,2-c]pyridine;3-[(4-fluorophenyl)sulfonyl]-5-(4-methylpiperazin-1-yl)-1H-pyrrolo[3,2-b]pyridine;3-[(2-chlorophenyl)sulfonyl]-5-(4-propylpiperazin-1-yl)-1H-pyrrolo[2,3-b]pyridine;3-[(4-aminophenyl)sulfonyl]-5-piperazin-1-yl-1H-pyrrolo[2,3-b]pyridine;2-methyl-3-(phenylsulfonyl)-5-piperazin-1-yl-1H-pyrrolo[2,3-b]pyridine;4-chloro-3-(phenylsulfonyl)-5-piperazin-1-yl-1H-pyrrolo[2,3-b]pyridine;7-fluoro-3-(phenylsulfonyl)-5-piperazin-1-yl-1H-pyrrolo[2,3-b]pyridine;6-fluoro-3-(phenylsulfonyl)-5-piperazin-1-yl-1H-pyrrolo[2,3-c]pyridine;6-(4-benzylpiperazin-1-yl)-3-(phenylsulfonyl)-1H-pyrrolo[3,2-c]pyridine;6-(4-methylpiperazin-1-yl)-3-(phenylsulfonyl)-1H-pyrrolo[3,2-b]pyridine;3-(phenylsulfonyl)-6-(4-propylpiperazin-1-yl)-1H-pyrrolo[2,3-b]pyridine;3-(phenylsulfonyl)-6-piperazin-1-yl-1H-pyrrolo[2,3-b]pyridine;4-(4-benzylpiperazin-1-yl)-3-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine;4-(4-methylpiperazin-1-yl)-3-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine;3-(phenylsulfonyl)-4-(4-propylpiperazin-1-yl)-1H-pyrrolo[3,2-c]pyridine;3-(phenylsulfonyl)-4-piperazin-1-yl-1H-pyrrolo[3,2-b]pyridine;3-(phenylsulfonyl)-7-piperazin-1-yl-1H-pyrazolo[4,3-b]pyridine;3-[(1-naphthyl)sulfonyl]-5-piperazin-1-yl-1H-pyrazolo[4,3-b]pyridine;3-(phenylsulfonyl)-5-piperazin-1-yl-1H-pyrazolo[4,3-b]pyridine;3-[(3-fluorophenyl)sulfonyl]-5-piperazin-1-yl-1H-pyrazolo[4,3-b]pyridine;3-[(3-fluorophenyl)sulfonyl]-7-piperazin-1-yl-1H-pyrazolo[4,3-b]pyridine;3-(phenylsulfonyl)-7-piperazin-1-yl-1H-pyrazolo[3,4-c]pyridine;3-[(1-naphthyl)sulfonyl]-7-piperazin-1-yl-1H-pyrazolo[3,4-c]pyridine;3-(2-thienyisulfonyl)-7-piperazin-1-yl-1H-pyrazolo[3,4-c]pyridine;3-[(3-fluorophenyl)sulfonyl]-1-methyl-7-piperazin-1-yl-1H-pyrazolo[3,4-c]pyridine;3-[(3-fluorophenyl)sulfonyl]-7-piperazin-1-yl-1H-pyrazolo[3,4-c]pyridine;3-(phenylsulfonyl)-5-piperazin-1-yl-1H-pyrazolo[3,4-c]pyridine;3-[(1-naphthyl)sulfonyl]-5-piperazin-1-yl-1H-pyrazolo[3,4-c]pyridine;3-(phenylsulfonyl)-7-piperazin-1-yl-1H-pyrazolo[4,3-c]pyridine;3-[(1-naphthyl)sulfonyl]-7-piperazin-1-yl-1H-pyrazolo[4,3-c]pyridine;3-(2-thienyisulfonyl)-7-piperazin-1-yl-1H-pyrazolo[4,3-c]pyridine;3-[(3-fluorophenyl)sulfonyl]-1-methyl-7-piperazin-1-yl-1H-pyrazolo[4,3-c]pyridine;3-[(3-fluorophenyl)sulfonyl]-7-piperazin-1-yl-1H-pyrazolo[4,3-c]pyridine;3-(phenylsulfonyl)-5-piperazin-1-yl-1H-pyrazolo[3,4-b]pyridine;3-[(1-naphthyl)sulfonyl]-5-piperazin-1-yl-1H-pyrazolo[3,4-b]pyridine;3-(2-thienylsulfonyl)-5-piperazin-1-yl-1H-pyrazolo[3,4-b]pyridine;3-[(3-fluorophenyl)sulfonyl]-1-methyl-5-piperazin-1-yl-1H-pyrazolo[3,4-b]pyridine;3-[(3-fluorophenyl)sulfonyl]-5-piperazin-1-yl-1H-pyrazolo[3,4-b]pyridine;a stereoisomer thereof; and a pharmaceutically acceptable salt thereof.